Developing technology to target therapeutic agents to cancer cells, while sparing normal cells, is a promising approach to improved treatment. The specific targeting reagents of choice are monoclonal antibodies and their derivatives. Currently there is a good selection of such molecules that bind to highly expressed tumor antigens. The anticancer antibodies Rituxan and Herceptin have been approved by the FDA for use as therapeutic drugs, and several more antibody-based drugs are expected to be approved soon. The binding affinities of many antibodies to characteristic cancer antigens are strikingly low; they depend on multivalent binding for their practical utility. For this reason, the utility of engineered proteins with single binding sites-such as single chain Fv molecules or Fab fragments-is limited. The use of modern combinatorial genetic techniques has led to improvements in the antigen-binding properties of engineered proteins, but further advances are needed. We propose a combined genetic/chemical approach to radically improve one such ligand/receptor interaction to the point of specific, irreversible binding. This research will ultimately lead to products that are themselves therapeutic drugs, or that serve as the first step in targeting drugs, radionuclides, or other effectors, to sites of disease. PROPOSED COMMERCIAL APPLICATION: Target-selective, irreversibly bindig platform for drug delivery, suitable for use in targeted therapy, radiotherapy, prodrug delivery, and other applications where long-lived specific binding is preferred.